Principal Investigator/Program Director (Last, first, middle): Xu, Huanbin! PROJECT SUMMARY / ABSTRACT Maternal HIV infection poses high risks for infecting infants during pregnancy, predisposing abnormalities of antibody responses to immunization and poor health outcomes in infants, especially during their first year of life, albeit the majority of newborn infants remain uninfected, suggesting that maternal HIV infection compromises early immune system development and function. In proposal, we hypothesize that HIV infection during pregnancy impairs maternal/fetal communications through persistent inflammatory signals and pathological placenta, which compromise fetal development of systemic and lymphoid tissues, and subsequent antibody responses to vaccines in early-life. We also hypothesize that administering suppressive combined antiretroviral therapy (cART) may directly restore fetal immune development, and improve immune function in infants. Using non-human primate models, we have discovered many unexpected facts regarding the immunology and pathogenesis of HIV and primate neonatal immunology. We have shown that SIV-infected infants rapidly and selectively lose mucosal innate lymphoid cells (ILC1/NK, ILC3, ILC17, ILC22) and regulatory T cells resulting in dysfunctional germinal center (GC) reactions and subsequently, inadequate antibody responses. Our most recent studies show that normally, GC B cells, rapidly aggregate in follicles within days after birth, highly co- express Ki67, Bcl-6 and EZH2. However, these EZH2+ GC B cells do not appear in lymph nodes of SIV- infected neonates, accompanied by impaired lymphoid architecture and inadequate Ab responses. Studies indicate EZH2 is responsible for epigenetic silencing of the cyclin dependent kinase inhibitor (CDK inhibitor, cell cycle suppression) via trimethylation of histone H3 lysine 27 (H3K27me3). Here we will investigate the cellular and molecular mechanisms behind the impaired generation of antibody responses in infants born to SIV-infected dams through detailed examinations of neonatal and infant mucosal and systemic lymphoid tissues and their development and function. Given converging data that the growing populations of HIV- exposed uninfected (HEU) infants have immunologic impairments, it is clear that there are many fundamental gaps in our understanding of how maternal HIV infection may influence placental function, fetal immune development, and why HEU infants have defective Ab responses. This proposal is designed to address early development of systemic and lymphoid compartments in neonates exposed to maternal HIV infection: a) determining the alterations of placental immunology; b) evaluating neonatal immune development and function of systemic and lymphoid compartments in the context of maternal HIV infection, and; c) exploring the cellular and molecular mechanisms involved in compromised Ab responses to routine vaccinations in infants exposed to maternal HIV infection, with and without short-term cART during pregnancy. The knowledge gained in this proposal will be of tremendous importance for optimizing HIV prevention, and improving immunization regimens for infants when exposed to maternal HIV infection.